The SQ HDM SLIT‐Tablet is safe and well tolerated in patients with House Dust Mite allergic rhinitis with or without asthma: A “real‐life” French study

Abstract Background The SQ House Dust Mite (HDM) SubLingual ImmunoTherapy (SLIT)‐Tablet (Acarizax) is the only allergen immunotherapy authorized by European regulatory authorities to treat HDM‐induced allergic asthma (AA) that is not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM allergic rhinitis (AR). The aim of this study was to add evidence on the safety of the SQ HDM SLIT‐Tablet in patients with AR, alone or with AA, under real‐life conditions. Methods This was a French “real‐life”, multicenter, non‐comparative, longitudinal, prospective study. It included patients initiating the SQ HDM SLIT‐Tablet for either persistent moderate‐to‐severe HDM AR or AA not well‐controlled by inhaled corticosteroids and associated with mild‐to‐severe HDM AR. Adverse Events (AEs) were collected at the first intake and throughout the study. Logistic regression was used to compare safety according to asthma control before treatment initiation. Results Between May 09, 2018 and May 29, 2019, 1526 patients were enrolled at 185 sites and 1483 were included in the safety population (SAF). Of them, 33.6% had suspected clinical manifestations of AA. Asthma was uncontrolled for 18.2% of the patients, partially controlled for 27.9% and well‐controlled for 53.8%. Overall, 31.9% of the SAF patients experienced at least one AE. The percentage of patients with AEs was 29.9% among patients with AR alone and 35.9% among those with AA (p = 0.0193). No significant difference was observed in the rate of AE or SAE depending on asthma control at inclusion (2.2% of SAEs reported for patients with uncontrolled asthma, 1.4% for partly controlled and 1.1% for well‐controlled). Conclusions The overall results indicate a good SQ HDM SLIT‐Tablet safety profile consistent with that reported in previous studies, regardless of asthma control.


M O T S -C L É S
Asthme, Immunothérapie, Traitement de l'allergie

| INTRODUCTION
The prevalence of allergic rhinitis (AR) continues to increase worldwide, and it has been estimated that 500 million people suffer from AR and 300 million from asthma. 1,2 AR is thought to affect 24.5% of the French population sensitization to HDM is found in 49% of subjects with a clinical diagnosis of AR in western Europe. 3 Among patients receiving allergen immunotherapy (AIT) for AR in France, 66.3% are treated with HDM allergenic extract. 4 The association between AR and allergic asthma (AA) is well established [5][6][7] and exposure to HDM allergens is associated with an increased risk of developing asthma and exacerbations of asthma. 8,9 In the European Community Respiratory Health Survey, the percentage of asthma attributable to HDM sensitization was 18.2% in the overall population and 12%-48% in various study centers in France. 10 More broadly, with the change in western European lifestyles, citizens spend most time indoors and therefore are increasingly exposed to the indoor allergens known to be drivers of more severe phenotypes of AA. 11 The only etiological treatment of HDM respiratory allergy is AIT. AIT can be administered either subcutaneously (SCIT) or sublingually (SLIT). In the recent EAACI guidelines, 12

| Study design and population
This was a "real-life", non-interventional, French, multicenter, noncomparative, longitudinal, prospective and descriptive study conducted between May 2018 and September 2020. Patients had to be aged between 18 and 65 years, with a clinical history and positive test of HDM sensitization (skin prick test and/or specific Immunoglobulin E [IgE]), and starting the SQ HDM SLIT-Tablet for either of these two indications: persistent moderate-to-severe HDM AR despite the use of symptom-relieving medication; or HDM AA not well-controlled by inhaled corticosteroids and associated with mild-to-severe HDM AR.
The decision to treat and the choice of indication had to be made before the patient entered the study and was left to the physician's discretion.
Patients who had received any HDM immunotherapy in the 12 months prior to the study start were not included.
Patients were only included in the study after the decision to prescribe the SQ HDM SLIT-Tablet had been taken and routine examinations and inquiries had been conducted and documented.
Physicians involved in the study comprised allergists, pulmonologists and ear, nose and throat (ENT) specialists. The study was proposed consecutively and exhaustively to all patients who met the eligibility criteria and had consulted the participating physicians during the 1-year inclusion period, until the number of patients required for each group was obtained (competitive recruitment). The number of visits and examinations was at the physician's discretion, but patients were expected to attend up to four visits over a period of approximatively 12 months: two mandatory face-to-face visits at the start of the study, during which the SQ HDM SLIT-Tablet was first administered and at the end; between these visits, two more were optional in line with the physician's real-life practice to monitor tolerance and compliance. The last visits of the last patients were held more than a year after inclusion because of the COVID-19 pandemic: there was a lockdown in France when these last visits should have taken place.
The symptom-relieving medications against rhinitis, conjunctivitis or asthma taken during the last 12 months before the inclusion visit were recorded. The medical assessment of the rhinitis followed ARIA guidance and included the frequency and severity of symptoms: the AR could be classified as intermittent or persistent according to the frequency of symptoms per week, and as mild or moderatesevere depending on its severity. The control level of AR symptoms was assessed using the allergic rhinitis control test (ARCT) patient questionnaire. 17 Asthma symptom control was assessed according to the GINA control score and the asthma control test (ACT) patient questionnaire. Although it was recommended to physicians that the SQ HDM SLIT-Tablet be first administered under medical supervision, other modalities could be adopted, and therefore details of the first administration (during or after the first visit/supervised or unsupervised) were recorded by the investigator. Adverse events (AEs) and Serious Adverse Events (SAEs) were recorded at all planned and unscheduled visits. The severity and seriousness of the AE was judged by the investigator.

| Objectives
The main objective of the study was to assess the tolerance and safety of the SQ HDM SLIT-Tablet in a "real-life" setting.

| Sample size
The number of patients had been calculated independently for each physician group. To achieve sufficient accuracy (4.9%) for each specialty type, it was planned to include 500 patients per physician group (allergists, pulmonologists and ENT). Groups were compared (AR vs. AA; physician specialty; study completed vs. premature discontinuation) using the chi 2 test or Fisher's exact test (qualitative variables), and Student's t-test (quantitative variables). The significance level was set at

| Statistical methods
Comparisons between groups for safety analyses were made using a logistic model for items with data for 15 patients or more. The items considered for the regression analysis were patients with at least: one AE, one AE possibly related to the SQ HDM SLIT-Tablet, one AE with severity = mild, one AE with severity = moderate, one AE with severity = severe, one AE leading to corrective treatment, one AE leading to temporary interruption of the SQ HDM SLIT-Tablet, one AE leading to discontinuation of the SQ HDM SLIT-Tablet, and one AE leading to no action taken on administration of the SQ HDM SLIT-Tablet.
AEs were also analyzed according to the time of occurrence (on the day of first administration of the SQ HDM SLIT-Tablet or during the entire study period).

| Ethical considerations
The study was conducted in accordance with Good Pharmacovigi-

| Baseline demographic and disease characteristics
Patient baseline characteristics are presented in Table 1. Over half of the patients were female (58.5%) and the mean (SD) age was 34.2 (11.5) years. The mean (SD) body mass index (BMI) was 24.1 (4.2) kg/ m 2 : 24.0% of patients were overweight and 8.9% were obese. Most patients (79.9%) were non-smokers.
The percentage of patients with a sensitization other than HDM (tree, grass, weed, epithelia from furry animals, molds, food) was significantly greater among AA patients than among AR alone DEMOLY ET AL.

| Modalities of the SQ HDM SLIT-Tablet administration
Most (94.9%) patients took the first SQ HDM SLIT-Tablet immediately (during the first visit) and did so under medical supervision (97.9%).

| Safety
Overall, 31.9% of the SAF patients experienced 982 AEs over the course of the study; 872 of them were possibly related to the SQ HDM SLIT-Tablet and were reported by 29.4% of patients.
The percentage of patients with at least one AE was 35.9% among those with AA and 29.9% among those with AR alone (p = 0.0193; Table 2).
The percentage of patients with at least one AE according to    (Table S3).
The distribution of patients with at least one AE was similar across the GINA 2017 steps and a logistic regression model revealed that the probability of experiencing an AE, regardless of the severity, was not significantly associated with them (data not shown).

| DISCUSSION
The primary aim of this study was to assess the safety and tolerability  Our results on the nature and severity of AEs also coincide with previous findings, and the most frequently reported AEs were throat irritation (9.1%), oral pruritus (8.6%) and ear pruritus (3.4%). The The tolerance and safety profile observed in this study was also similar to the one observed in the EPIGRAM study, in which 504 adults and children received GRAZAX® for the treatment of grass pollen-induced rhinitis and conjunctivitis under real-life conditions. 21 All but one patient had severe allergic rhino-conjunctivitis. Adverse drug reactions were reported by 43% of the patients and serious adverse drug reactions (uvular edema, laryngeal edema and periodontitis) were reported in three patients. In the EPIGRAM study, asthma was associated with the allergic rhino-conjunctivitis in 168 cases, but it was mostly controlled (89% of patients).
Subgroup analyses revealed no statistically significant difference in the risk of experiencing treatment-related AEs depending on the asthma control. In addition, subjects with partly controlled or uncontrolled asthma were no more likely to experience AEs that would lead to discontinuation of the SQ HDM SLIT-Tablet or to taking a corrective treatment than subjects with controlled asthma. These results are wholly consistent with those based on pooled safety data from P003 and MT-04 trials reported by Emminger et al. 16 The There is little evidence on the safety of the SQ HDM SLIT-Tablet for the treatment of patients with severe, unstable, uncontrolled asthma, and the presence of such a condition is a contraindication.
This study, with 18.9% of patients having uncontrolled asthma according to the ACT scale, will enable complementing data from further studies and strengthen the picture on the SQ HDM SLIT-Tablet's potential benefits and disadvantages for the indication.
This study had a very large sample size, ensuring representativeness of the French AR population with or without AA. However, potential limitations were the lack of quality control surrounding data collection and the loss of patients. All data must be considered, acknowledging that for some of the patients lost to follow-up, no complete information was available at the time of their discontinuation.

| CONCLUSIONS
In this study, the overall results indicate a good safety and tolerability profile of the SQ HDM SLIT-Tablet, consistent with that reported in previous studies for the treatment of patients with HDM-induced AR.
In addition, with the favorable safety profile for the treatment of T A B L E 3 Adverse events depending on asthma control according to GINA Score-SAF population with asthma as the clinical manifestation (N = 499) patients with AA regardless of control in real-life settings, the SQ HDM SLIT-Tablet represents a good treatment option for controlled or partly controlled asthmatic patients. Data from this study question the relevance of the current absolute contraindication in uncontrolled asthma.